Randomized, Double-Blind, Placebo-Controlled Study of...
Transcript of Randomized, Double-Blind, Placebo-Controlled Study of...
Randomized, Double-Blind, Placebo-ControlledRandomized, Double-Blind, Placebo-ControlledStudy of Intramyocardial CD34+ Cell Therapy forStudy of Intramyocardial CD34+ Cell Therapy for
Refractory AnginaRefractory Angina
Douglas W. Losordo, M.D.on behalf of ACT34-CMI
Investigators
Northwestern University, Chicago, USA
Presenter Disclosure Information
Douglas Losordo, M.D.
The following relationships exist related to thispresentation:
• Study Sponsored by Baxter Healthcare
• Dr. Losordo was previously a paid consultant for BaxterHealthcare, receiving “modest” consulting fees by ACCdefinition.
Tempa CurryUniversity of FloridaCarl Pepine
Deb WallerSt. Luke'sSteven Port
Amy OllingerU of Iowa Healthcare – Iowa CityPhilip Horwitz
Mark AndersonNeal Weintraub
M. Sue HusemanUniversity of Cincinnati Medical CenterNeal Weintraub
Terri KellermanHoly Cross Hospital – Fort LauderdaleAlan Niederman
Leanne GoodwinFlorida HospitalAndrew Taussig
Poorna NagarajanRush University Medical CenterGary Schaer
Heather CatchpoleScripps Clinic – La JollaRichard Schatz
Lisa BaxendellUPMC - PittsburghJoon Sup Lee
Shirley MordenShands Jacksonville Medical Center - JacksonvilleTheodore BassMarco Costa
Rachel OlsonKaren HarveyPatti Mitchell
Minneapolis Heart Inst. - MSPTim HenryJay Traverse
Main Study CoordinatorInstitutionInvestigatorACT34-CMI STUDY SITES
Valerie CwiklinskiUniversity Hospitals of ClevelandDaniel Simon
Sherrie WolfNorthwestern - ChicagoCharles Davidson
Rebecca AllenSt. Joseph’s Research InstituteNicholas Chronos
Dolores ReynoldsCornell University, Weill College of MedicineChiu Wong
Jeanie SohnNY Presbyterian Hospital - NYWarren Sherman
Petros OkubagziWashington Hospital CenterRon Waksman
Cristina BrueggemanMassachusetts General HospitalKen Rosenfield
Maria PerlasYvonne StrawaStanford University HospitalAlan Yeung
Susan DeramusCardiology P.C., BirminghamFarrell Mendelsohn
Cassondra Vander ArkUniversity of Wisconsin-MadisonAmish Raval
Kathy BuszekThe Lindner Clinical Trial CenterDean Kereiakes
Jacklyn GentryMayo Clinic - ScottsdaleDavid Fortuin
Melissa AntonellisSt. Elizabeth’s - BostonPeter Soukas
Candice KellyArizona Heart - PhoenixRobert StrumpfZaki Lababidi
Nabil Dib
Jennifer HudachekSwedish Seattle HospitalPaul Huang
Main Study CoordinatorInstitutionInvestigator
ACT34-CMI STUDY SITES
ACT34-CMI Core Labs
Exercise Treadmill Time (ETT) Core Lab Dr. Ernest Gervino
Cardiovascular Core Laboratories – SPECT James Udelson, MD
ACT34-CMI Core Labs
Magnetic Resonance Imaging / PERFUSE Dr. Evan Appelbaum
Quality of Life Dr. David Cohen
Data Safety Monitoring Board Dr. Jeffrey Brinker, Chair Dr. Kenneth Ellenbogen Dr. Armand Keating Dr. George Vetrovec Dr. James Dziura
Brigham and Women’s Hospital, Clinical EndpointCommittee Dr. Marc Pfeffer Dr. Akshay Desai Dr. Peter Finn
Study Logistics
Duke Clinical Research Institute (statistical analysis) Robert Harrington, MD Karen Pieper, M.S. Robert Clare, M.S.
Biologics Delivery Systems: NOGA Mapping Support
Study Logistics
1 x 10^5 CD34+ cells/kg (n = 55)
5 x 10^5 CD34+ cells/kg (n = 56)
Endomyocardial Mapping and Injection with NOGAIsolex selected CD34+ cells / Placebo Rx
Cell Mobilization (GCSF 5mcg/kg/d x 5d)Apheresis on Day 5
Follow-up Safety and Efficacy Assessments:1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months
MRI at 6 months, SPECT at 6 & 12 months
Screening and Baseline Visits
Placebo(n = 56)
Randomization
Phase II ACT34–CMI Study Design
Subject population (n=167)
• 21-80 yrs• CCS class III or IV Angina• Attempted “best” medical
therapy• Non-candidate for
Surgical/Perc. revasc.• Ischemia on SPECT• 3-10 min. mod. Bruce
protocol with angina oranginal equivalent atbaseline
Endpoints
Safety
Adverse event reporting, MACE, physical examination, vital signs,ECHO, laboratory parameters, revascularization procedures,hospitalization rates for cardiac related admissions and EmergencyDepartment/Acute Care Service visits for cardiac related admissionswill assess safety.
Bioactivity
Primary Efficacy variable is frequency of angina episodes per week,when comparing subjects receiving injection of CD34+ cells to placebo.Secondary Efficacy variables are divided into two categories, symptomrelief and myocardial perfusion, and function measurement endpoints.Symptom Relief: ETT, anti-anginal medication, pedometermeasurements, CCS functional class and QOL [SAQ, SF-36, DyspneaQuestionnaire, Euro 5 Questionnaire], and the combined rate of MACEevents. Myocardial perfusion and function measurements: SPECT andcardiac MRI.
Enrollment/Demographics
Enrollment First subject enrolled (screened): 04 April 2006 First subject treated: 18 May 2006 Last subject screened: 15 Jan 2008 Last subject treated: 13 March 2008 Last subject 6 Mo follow up: 01 Oct 2008 Last subject 12 Mo follow up: 05 Mar 2009
321 subjects signed informed consent 167 subjects underwent injection procedure 162 subjects completed 6 mo follow up
Enrollment/Demographics
Control 1x105 5x105 p-value
Age%Female%Diabetic
61.810.755.4
61.316.447.3
59.812.555.4
0.4710.6680.617
%Prior MI# of Prior PCI
# of Prior CABG
73.7%2.7 (3.8)1.4 (0.6)
74.1%3.2 (2.8)1.2 (0.6)
77.6%2.8 (2.7)1.2 (0.7)
0.9030.6680.410
LVEF(SPECT) mean(SD)
59.8(14.6)
58.9(14.2)
60.6(13.3)
0.820
ACE-IBeta Blocker
Statin
58.9%98.2%91.1%
52.7%92.7%90.9%
57.1%91.1%89.3%
0.8190.2631.000
Safety
Procedural Events 2 Perforations (1.2%) 1 Death (0.6%)
Major Adverse Cardiac Events (12 Months)
0.4165.4%7.3%12.5%Death, MI, Post-PCI MI, Urgent
Revasc
0.1238.9%9.1%21.4%Death, MI,Urgent Revasc,
Worse CHF, ACS
1.0001.8%1.8%3.6%MI pre/injection
Control 1x105 5x105 p-value
Any MACE 25.0% 12.7% 14.3% 0.194
Death, MI,Urgent Revasc
10.7% 7.3% 5.4% 0.594
Any MI 7.1% 9.1% 5.4% .707
Anginal Episodes per WeekAnginal Episodes per WeekChange from baseline at 6 monthsChange from baseline at 6 months
P=0.14
ACT-34 CMI: Reduction in AnginaACT-34 CMI: Reduction in Angina
Poisson Regression with Extra VariabilityPoisson Regression with Extra Variability
Anginal Episodes per WeekAnginal Episodes per WeekChange from baseline at 6 monthsChange from baseline at 6 months
P=0.04
ACT-34 CMI: Reduction in Angina
Analysis of Variance (ANOVA)Analysis of Variance (ANOVA)
Total ETT TimeTotal ETT TimeChange from baseline at 6 monthsChange from baseline at 6 months
Sec
onds
p=0.013
ACT-34 CMI: Increase in ExerciseACT-34 CMI: Increase in Exercise TimeTime
Time to AnginaTime to AnginaChange from baseline at 6 monthsChange from baseline at 6 months
p=0.247
ACT-34 CMI: Increase in Time to Angina
Time to Resolution of AnginaTime to Resolution of Angina
ACT-34 CMI: Reduction in Time to Resolution of AnginaACT-34 CMI: Reduction in Time to Resolution of Angina
Change in Time to Resolution of AnginaChange in Time to Resolution of Angina
p=0.048
ACT-34 CMI: More Rapid Resolution of Angina
Rate-Pressure Product at Resolution ofRate-Pressure Product at Resolution of AnginaAngina
ACT-34 CMI: Increased RPP at Resolution of AnginaACT-34 CMI: Increased RPP at Resolution of Angina
Change in Rate-Pressure ProductChange in Rate-Pressure Productat Resolution of Anginaat Resolution of Angina
p=0.516
ACT-34 CMI:ACT-34 CMI: IncreaseIncrease in RPP at Resolution of Anginain RPP at Resolution of Angina
Other Outcomes
Seattle Angina Questionnaire SPECT CCS Angina Classification SF36
Summary
Feasibility Phase 2 study successfully enrolled 167 pts at 26
centers across US Safety
No evidence of harm by injection of autologousCD34+ cells; Net trends toward decreased MACE
Summary (2)
Bioactivity Angina frequency ETT
Total Time increased Time to Resolution of Angina Time to Angina Change in RPP at resolution of Angina
SPECT CCS Class, SAQ, SF36
Conclusions
167 “no-option” refractory angina pts enrolled in RCTof intramyocardial autologous CD34+ stem celltherapy
Safety profile appears acceptable Significant improvement in ETT - first in this
population Reduced angina; trend vs. significant
Ongoing
Awaiting 12 month data 2nd year follow up study
Limitations
Phase 2 study - not conclusive 12 mo data pending
Questions
Effects of GCSF Non-linear dose response
Thank you for your attentionThank you for your attention